In Australia, cases of shigellosis usually occur in returned travelers from regions of shigellosis endemicity or in men who have sex with men. Resistance to multiple antibiotics has significantly increased in Shigella sonnei isolates and represents a significant public health concern. We investigate an outbreak of multidrug-resistant S. sonnei in Victoria, Australia. We undertook whole-genome sequencing of 54 extended-spectrum-beta-lactamase (ESBL)-producing S. sonnei isolates received at the Microbiological Diagnostic Unit Public Health Laboratory between January 2019 and March 2020. The population structure and antimicrobial resistance profiles were identified by genomic analyses, with 73 previously characterized Australian S. sonnei isolates providing context. Epidemiological data, including age and sex of the shigellosis cases, were also collected. There was a significant increase in cases of ESBL S. sonnei from July 2019. Most of the ESBL S. sonnei isolates (65%) fell within a single cluster that was predominantly comprised of male cases that were characterized by the presence of the blaCTX-M-27 gene conferring resistance to extended-spectrum cephalosporins. These isolates were also multidrug resistant, including resistance to azithromycin and co-trimoxazole and reduced susceptibility to ciprofloxacin. Our data uncovered a prolonged clonal outbreak of ESBL S. sonnei infection that was likely first introduced by returned travelers and has subsequently been circulating locally in Australia. The emergence of a local outbreak of ESBL S. sonnei with a multidrug-resistant profile, including reduced susceptibility to ciprofloxacin, represents a significant public health threat.To explore the mutational possibilities of insertions and deletions (indels) in the Klebsiella pneumoniae carbapenemase (KPC) beta-lactamase, we selected for ceftazidime-avibactam-resistant mutants. Of 96 screened mutants, we obtained 19 indels (2 to 15 amino acids), all located in the loops surrounding the active site. Three antibiotic susceptibility phenotypes emerged an extended-spectrum-beta-lactamase-like phenotype, an activity restricted to ceftazidime, and a carbapenem-susceptible KPC-like phenotype. Tolerance for indels reflects the evolvability of KPC beta-lactamase, which could challenge the therapeutic management of patients.Alternative therapeutic options are urgently needed against multidrug-resistant Escherichia coli infections, especially in situations of preexisting tigecycline and colistin resistance. Here, we investigated synergistic activity of the antiretroviral drug zidovudine in combination with tigecycline or colistin against E. coli harboring tet(X) and mcr-1 in vitro and in a murine thigh infection model. Zidovudine and tigecycline/colistin combinations achieved synergistic killing and significantly decreased bacterial burdens by &gt;2.5-log10 CFU/g in thigh tissues compared to each monotherapy.Given that it is unlikely that randomized clinical trials will yield answers for treating the most challenging bacteremic infections caused by methicillin-resistant Staphylococcus aureus, clinicians, microbiologists, and pharmacists will have to cooperate to discover novel ways to select successful individualized antimicrobial therapy for these patients. An example of such a strategy was demonstrated in the identification and utilization of imipenem/cilastatin plus fosfomycin to treat a particularly recalcitrant MRSA bacteremia and spinal abscess.Cefuroxime (CXM) is an antibiotic recommended for surgical site infection prevention in cardiac surgery. However, the dosing regimens commonly used do not sustain therapeutic concentrations throughout surgery. https://www.selleckchem.com/products/dabrafenib-gsk2118436.html The aim of this study was to conduct a population analysis of CXM pharmacokinetics (PK), and to propose an optimized dosing regimen. Adult patients undergoing cardiac surgery under cardiopulmonary bypass (CPB) received a 1,500?mg CXM intravenous bolus followed by a 750?mg bolus at CPB priming, then every 2 h thereafter. Model-based PK simulations were used to develop an optimized dosing regimen and evaluate its efficacy in attaining various concentration thresholds, including those recommended in US and European guidelines. In total, 447 CXM measurements were acquired in 50 patients. A two-compartment model best fit the data, with total body weight and creatinine clearance determining interpatient variability in the central and peripheral volumes of distribution, and in elimination clearance, respectively. Using our optimized dosing regimen, different dosing schemes adapted to body weight and renal function were calculated to attain total concentration thresholds ranging from 12 to 96?mg/liter. Our simulations showed that the dosing regimens recommended in US and European guidelines failed to maintain concentrations above 48?mg/liter. Our individualized dosing strategy was capable of ensuring therapeutic CXM concentrations conforming to each target threshold. Our model yielded an optimized CXM dosing regimen adapted to body weight and renal function, and sustaining therapeutic concentrations consistent with each desired threshold. The optimal target concentration and necessary duration of its maintenance in cardiac surgery still remain unclear.Dihydroartemisinin-piperaquine (DHA-PQ) provides highly effective therapy and chemoprevention for malaria in pregnant African women. PQ concentrations of &gt;10.3?ng/ml have been associated with reduced maternal parasitemia, placental malaria, and improved birth outcomes. We characterized the population pharmacokinetics (PK) of PQ in a post hoc analysis of human immunodeficiency virus (HIV)-infected and -uninfected pregnant women receiving DHA-PQ as chemoprevention every 4 or 8?weeks. The effects of covariates such as pregnancy, nutritional status (body mass index [BMI]), and efavirenz (EFV)-based antiretroviral therapy were investigated. PQ concentrations from two chemoprevention trials were pooled to create a population PK database from 274 women and 2,218 PK observations. A three-compartment model with an absorption lag best fit the data. Consistent with our prior intensive PK evaluation, pregnancy and EFV use resulted in a 72% and 61% increased PQ clearance, compared to postpartum and HIV-uninfected pregnant women, respectively.